Reporting of harm in randomized controlled trials evaluating stents for percutaneous coronary intervention

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to assess the reporting of harm in randomized controlled trials evaluating stents for percutaneous coronary intervention.</p> <p>Methods</p> <p>The study design was a methodological systematic review of randomized controlled trials. The data sources were MEDLINE and the Cochrane Central Register of Controlled Trials. All reports of randomized controlled trials assessing stent treatment for coronary disease published between January 1, 2003, and September 30, 2008 were selected.</p> <p>A standardized abstraction form was used to extract data.</p> <p>Results</p> <p>132 articles were analyzed. Major cardiac adverse events (death, cardiac death, myocardial infarction or stroke) were reported as primary or secondary outcomes in 107 reports (81%). However, 19% of the articles contained no data on cardiac events. The mode of data collection of adverse events was given in 29 reports (22%) and a definition of expected adverse events was provided in 47 (36%). The length of follow-up was reported in 95 reports (72%). Assessment of adverse events by an adjudication committee was described in 46 reports (35%), and adverse events were described as being followed up for 6 months in 24% of reports (n = 32), between 7 to 12 months in 42% (n = 55) and for more than 1 year in 4% (n = 5). In 115 reports (87%), numerical data on the nature of the adverse events were reported per treatment arm. Procedural complications were described in 30 articles (23%). The causality of adverse events was reported in only 4 articles.</p> <p>Conclusion</p> <p>Several harm-related data were not adequately accounted for in articles of randomized controlled trials assessing stents for percutaneous coronary intervention.</p> <p>Trials Registration</p> <p>Trials manuscript: 5534201182098351 (T80802P)</p

Image-based Search and Retrieval for Biface Artefacts using Features Capturing Archaeologically Significant Characteristics

Archaeologists are currently producing huge numbers of digitized photographs to record and preserve artefact finds. These images are used to identify and categorize artefacts and reason about connections between artefacts and perform outreach to the public. However, finding specific types of images within collections remains a major challenge. Often, the metadata associated with images is sparse or is inconsistent. This makes keyword-based exploratory search difficult, leaving researchers to rely on serendipity and slowing down the research process. We present an image-based retrieval system that addresses this problem for biface artefacts. In order to identify artefact characteristics that need to be captured by image features, we conducted a contextual inquiry study with experts in bifaces. We then devised several descriptors for matching images of bifaces with similar artefacts. We evaluated the performance of these descriptors using measures that specifically look at the differences between the sets of images returned by the search system using different descriptors. Through this nuanced approach, we have provided a comprehensive analysis of the strengths and weaknesses of the different descriptors and identified implications for design in the search systems for archaeology

Phosphatidylinositol 3-kinase (PI3K) pathway activation in bladder cancer

The phosphatidylinositol 3-kinase (PI3K) pathway is a critical signal transduction pathway that regulates multiple cellular functions. Aberrant activation of this pathway has been identified in a wide range of cancers. Several pathway components including AKT, PI3K and mTOR represent potential therapeutic targets and many small molecule inhibitors are in development or early clinical trials. The complex regulation of the pathway, together with the multiple mechanisms by which it can be activated, make this a highly challenging pathway to target. For successful inhibition, detailed molecular information on individual tumours will be required and it is already clear that different tumour types show distinct combinations of alterations. Recent results have identified alterations in pathway components PIK3CA, PTEN, AKT1 and TSC1 in bladder cancer, some of which are significantly related to tumour phenotype and clinical behaviour. Co-existence of alterations to several PI3K pathway genes in some bladder tumours indicates that these proteins may have functions that are not related solely to the known canonical pathway

ASPM and microcephalin expression in epithelial ovarian cancer correlates with tumour grade and survival

BACKGROUND: The clinico-pathological and molecular heterogeneity of epithelial ovarian cancer (EOC) complicates its early diagnosis and successful treatment. Highly aneuploid tumours and the presence of ascitic fluids are hallmarks of EOC. Two microcephalyassociated proteins, abnormal spindle-like microcephaly-associated protein (ASPM) and microcephalin, are involved in mitosis and DNA damage repair. Their expression is deregulated at the RNA level in EOC. Here, ASPM and microcephalin protein expression in primary cultures established from the ascites of patients with EOC was determined and correlated with clinical data to assess their suitability as biomarkers. METHODS: Five established ovarian cancer cell lines, cells derived from two benign ovarian ascites samples and 40 primary cultures of EOC derived from ovarian ascites samples were analysed by protein slot blotting and/or immunofluorescence to determine ASPM and microcephalin protein levels and their cellular localisation. Results were correlated with clinico-pathological data. RESULTS: A statistically significant correlation was identified for ASPM localisation and tumour grade, with high levels of cytoplasmic ASPM correlating with grade 1 tumours. Conversely, cytoplasmic microcephalin was only identified in high-grade tumours. Furthermore, low levels of nuclear microcephalin correlated with reduced patient survival. CONCLUSION: Our results suggest that ASPM and microcephalin have the potential to be biomarkers in ovarian cance

Maf1, a New Player in the Regulation of Human RNA Polymerase III Transcription

BACKGROUND: Human RNA polymerase III (pol III) transcription is regulated by several factors, including the tumor suppressors P53 and Rb, and the proto-oncogene c-Myc. In yeast, which lacks these proteins, a central regulator of pol III transcription, called Maf1, has been described. Maf1 is required for repression of pol III transcription in response to several signal transduction pathways and is broadly conserved in eukaryotes. METHODOLOGY/PRINCIPAL FINDINGS: We show that human endogenous Maf1 can be co-immunoprecipitated with pol III and associates in vitro with two pol III subunits, the largest subunit RPC1 and the α-like subunit RPAC2. Maf1 represses pol III transcription in vitro and in vivo and is required for maximal pol III repression after exposure to MMS or rapamycin, treatments that both lead to Maf1 dephosphorylation. CONCLUSIONS/SIGNIFICANCE: These data suggest that Maf1 is a major regulator of pol III transcription in human cells

Pressure pain sensitivity maps of the neck-shoulder and the low back regions in men and women

<p>Abstract</p> <p>Background</p> <p>Musculoskeletal pain in the low back and neck-shoulder regions is a major problem among the working population all over the world. The prevalence of musculoskeletal pain is found to be higher among women. Women also have lower pressure pain thresholds (PPTs) than men. Pressure pain topography aims at mapping the spatial distribution of PPT within a muscle in an attempt to track changes in mechanical sensitivity. In order to assess gender differences in the pain topography, it is necessary to map the distribution in both healthy men and women. The aim of this study was to assess PPT maps from the cervico-thoracic and lumbar regions in men and women.</p> <p>Methods</p> <p>Eleven men and eleven women without any known musculoskeletal disorders participated in the study. PPT was measured twice at 36 points over the trapezius muscle of the dominant arm, at 36 points over the trapezius muscle on the contralateral side and at 12 points over the spine between the left and right trapezius. Further, 11 points were measured over the erector spinae muscle on the left side of the spine between the first and the fifth lumbar vertebrae, 11 on the right side and 5 points on the spine itself. The measurements on each trapezius muscle were divided according to anatomical subdivisions. Three-way and two-way ANOVAs were used to analyse the differences in PPTs with the following factors: gender, locations and sub-divisions (only for cervico-thoracic region).</p> <p>Results</p> <p>There were no differences between left and right side in neither the cervico-thoracic nor the lumbar region, but there were (large effect) differences between the subdivisions in the trapezius with the lowest values in the upper part (P < 0.001; partial η²= 0.19). Women had (small effect) lower PPT in both cervico-thoracic and lumbar regions (P ≤ 0.001; partial η²= 0.02 for both regions), but gender had no effect on neither location nor subdivisions.</p> <p>Conclusions</p> <p>The pain topography was not found to be different between genders in the cervico-thoracic and lumbar regions. This study can be used as basis for further clinical studies on musculoskeletal disorders.</p

Decreased Mitochondrial DNA Mutagenesis in Human Colorectal Cancer

Genome instability is regarded as a hallmark of cancer. Human tumors frequently carry clonally expanded mutations in their mitochondrial DNA (mtDNA), some of which may drive cancer progression and metastasis. The high prevalence of clonal mutations in tumor mtDNA has commonly led to the assumption that the mitochondrial genome in cancer is genetically unstable, yet this hypothesis has not been experimentally tested. In this study, we directly measured the frequency of non-clonal (random) de novo single base substitutions in the mtDNA of human colorectal cancers. Remarkably, tumor tissue exhibited a decreased prevalence of these mutations relative to adjacent non-tumor tissue. The difference in mutation burden was attributable to a reduction in C∶G to T∶A transitions, which are associated with oxidative damage. We demonstrate that the lower random mutation frequency in tumor tissue was also coupled with a shift in glucose metabolism from oxidative phosphorylation to anaerobic glycolysis, as compared to non-neoplastic colon. Together these findings raise the intriguing possibility that fidelity of mitochondrial genome is, in fact, increased in cancer as a result of a decrease in reactive oxygen species-mediated mtDNA damage

Intravenous immunoglobulin and rituximab versus placebo treatment of antibody-associated psychosis: study protocol of a randomised phase IIa double-blinded placebo-controlled trial (SINAPPS2)

BACKGROUND: Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care. METHODS: We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2-4 consecutive days no later than 7 days from baseline. It will continue 4-5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2-3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response. DISCUSSION: The SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies. TRIAL REGISTRATION: ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017

Mast cell tryptase stimulates myoblast proliferation; a mechanism relying on protease-activated receptor-2 and cyclooxygenase-2

<p>Abstract</p> <p>Background</p> <p>Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2). The possibility that a tryptase/PAR-2 signaling pathway exists in skeletal muscle cell has never been investigated. The aim of this study was to evaluate whether tryptase can stimulate myoblast proliferation and determine the downstream cascade.</p> <p>Methods</p> <p>Proliferation of L6 rat skeletal myoblasts stimulated with PAR-2 agonists (tryptase, trypsin and SLIGKV) was assessed. The specificity of the tryptase effect was evaluated with a specific inhibitor, APC-366. Western blot analyses were used to evaluate the expression and functionality of PAR-2 receptor and to assess the expression of COX-2. COX-2 activity was evaluated with a commercial activity assay kit and by measurement of PGF₂α production. Proliferation assays were also performed in presence of different prostaglandins (PGs).</p> <p>Results</p> <p>Tryptase increased L6 myoblast proliferation by 35% above control group and this effect was completely inhibited by APC-366. We confirmed the expression of PAR-2 receptor <it>in vivo </it>in skeletal muscle cells and in satellite cells and <it>in vitro </it>in L6 cells, where PAR-2 was found to be functional. Trypsin and SLIGKV increased L6 cells proliferation by 76% and 26% above control, respectively. COX-2 activity was increased following stimulation with PAR-2 agonist but its expression remained unchanged. Inhibition of COX-2 activity by NS-398 abolished the stimulation of cell proliferation induced by tryptase and trypsin. Finally, 15-deoxy-Δ-^12,14-prostaglandin J₂(15Δ-PGJ₂), a product of COX-2-derived prostaglandin D₂, stimulated myoblast proliferation, but not PGE₂and PGF₂α.</p> <p>Conclusions</p> <p>Taken together, our data show that tryptase can stimulate myoblast proliferation and this effect is part of a signaling cascade dependent on PAR-2 activation and on the downstream activation of COX-2.</p

In Patients with Established RA, Positive Effects of a Randomised Three Month WBV Therapy Intervention on Functional Ability, Bone Mineral Density and Fatigue Are Sustained for up to Six Months

Functional ability is often impaired for people with rheumatoid arthritis (RA), rendering these patients highly sedentary. Additionally, patients with RA often take medication known to negatively affect bone mass. Thus improving functional ability and bone health in this group of patients is important. The aim of this study was to investigate the effects of whole body vibration (WBV) therapy in patients with stable, established RA. Thirty one females with RA were randomly assigned to a control group (CON, n = 15) who continued with their normal activities or a WBV group (n = 16) who underwent a three month WBV therapy intervention, consisting of 15 minutes of intermittent vibration, performed twice per week. Patients were assessed at baseline, three months, and three months post intervention for functional ability using the modified Health Assessment Questionnaire; for RA disease activity using the Clinical Disease Activity Index, for quality of life using self-report fatigue and pain scores; for physical activity profiles using accelerometry, and for BMD and body composition using DXA. Patients in both groups were matched for all variables at baseline. After the intervention period, functional ability was significantly improved in the WBV group (1.22(0.19) to 0.92(0.19), p = 0.02). Hip BMD was significantly reduced in the CON group (0.97(0.05) to 0.84(0.05) g.cm-2, p = 0.01), while no decreases were seen in the WBV group (1.01(0.05) to 0.94(0.05) g.cm-2, p = 0.50). Despite no change in RA disease activity in either group at either follow up, fatigue levels were improved in the WBV group (4.4(0.63) to 1.1(0.65), yet remained unchanged in the CON group at both follow ups (p = 0.01). Ten minute bouts of light to moderate physical activity were significantly reduced in the CON group after the intervention (2.8(0.61) to 1.8(0.64) bouts per day, p = 0.01), and were preserved in the WBV group (3.1(0.59) to 3.0(0.61) bouts per day, p = 0.70). Intermittent WBV shows promise for sustained improvements in functional ability, for attenuating loss of bone mass at the hip, as well as for decreasing fatigue in patients with established RA. TRIAL REGISTRATION: Pan African Clinical Trials Registry PACTR201405000823418